Differentiated thyroid carcinoma (DTC) is generally associated with excellent overall survival. A proportion of patients with advanced DTC may undergo dedifferentiation and progress to radioiodine-refractory (RAIR) disease. Although RAIR is typically linked to advanced stage, some patients develop RAIR despite presenting with low-stage disease. The characteristics of these patients remain insufficiently defined. This study aimed to compare clinicopathologic and biochemical features of low-stage DTC patients who develop RAIR with those who retain radioiodine (RAI) avidity.

A retrospective review was conducted on patients with low-stage DTC (T1–T3a, N0, M0; AJCC 8th edition) who underwent total thyroidectomy followed by radioiodine (RAI) therapy. All patients were classified as American Thyroid Association (ATA) low- or intermediate-risk. Aggressive histologic variants were excluded. RAIR status was determined using ATA 2015 criteria. Six RAIR patients were compared with twenty-two non-RAIR controls. Variables analyzed included age, sex, lymphovascular invasion (LVI), microscopic extrathyroidal extension (m-ETE), ATA risk category, stimulated thyroglobulin (Tg) before the first (Tg1) and second RAI (Tg2), Tg2/Tg1 ratio, BRAF V600E mutation, PIWIL1 expression, initial RAI activity, and first post-therapy scan uptake. Fisher’s exact and Mann–Whitney U tests were applied.

All patients presented with low-stage disease and non-aggressive histology. Age and sex distribution did not differ between groups. Stimulated Tg1 was significantly higher in the RAIR cohort compared with controls (median 59.65 vs. 6.65 ng/mL; p=0.0013). Stimulated Tg2 demonstrated a more pronounced divergence (median 35.35 vs. 0.06 ng/mL; p=0.0007). The Tg2/Tg1 ratio showed the strongest distinction (median 0.687 vs. 0.017; p=0.0047). Using a clinical threshold of >0.54, 4 of 6 RAIR cases exceeded the cutoff compared with 1 of 22 controls (p=0.0034). No significant differences were observed in LVI, m-ETE, BRAF mutation status, PIWIL1 expression, or ATA risk classification.

A subset of low-stage DTC patients developed RAIR despite otherwise favorable clinical and histologic features. Markedly higher stimulated Tg measurements and elevated Tg2/Tg1 ratio distinguished RAIR from non-RAIR patients, suggesting divergent biochemical behavior early in the disease course. These findings highlight the relevance of stimulated Tg assessment in identifying low-stage patients who may develop refractoriness and support more individualized postoperative surveillance strategies.